Cardiovascular disease (CVD) is a multifactorial disorder that involves both environmental and genetic factors; however, individual CVD susceptibility in this regard is not clearly understood. Recent studies on CVD susceptibility and resistance support the concept of groups of genes being involved in disease susceptibility - and while this is important in understanding that gene groups may be involved in influencing individual biological responses to an environmental challenge, they do not address the underlying issue of why these differences exist, nor how they might have developed. In this respect, current studies have not seriously considered the role of the mitochondrial DNA (mtDNA) and prehistoric selection factors that may have influenced mtDNA genetic selection, which today, potentially influence individual susceptibility to disease development. This proposal tests the hypothesis that mitochondrial genetic background significantly influences CVD susceptibility by determining the impact of different mitochondrial genetic backgrounds on nuclear gene expression and disease development in both human and animal models of CVD. Preliminary studies are provided that show mtDNA background significantly influences: i) mitochondrial function; ii) vascular function; iii) atherogenic susceptibility; iv) nuclear gene expression; and, v) can be associated with CVD incidence in humans. Studies are also presented that show distinct metabolic and oxidative capacities in human endothelial cells harboring either African or Caucasian mtDNA backgrounds. It is predicted that under normal physiological conditions these differences appear to have no functional outcome, but under stress (e.g. exposure to cytokines), their responses significantly differ with the cells harboring the African mtDNAs being more susceptible to uncontrolled ROS production and mitochondrial damage. Consequently, it is hypothesized that: Mitochondrial genetics and function are important factors in influencing individual CVD susceptibility. The studies herein represent a first step towards determining the potential role of mitochondrial genetics and function as a significant factor in modulating nuclear gene expression, and hence, in regulating individual biological responses to environmental and behavioral stimuli that may contribute to disease susceptibility. The proposed studies are novel in that they present a paradigm shift in the understanding of the role of the mitochondrion in disease risk and development.